Molecular Basis of Automaticity in the Myometrium

子宫肌层自动性的分子基础

• 批准号: 7314146
• 负责人: GLENNA C L BETT
• 金额: $ 7.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314146
• 关键词: Accounting; Age; Behavior; Behavioral; Biochemical Genetics; Biochemical Pathway; Biochemistry; Birth; Blindness; Cations; Cells; Cerebral Palsy; Characteristics; Class; Communication; Complex; Condition; Coupling; Cyclic Nucleotides; Data; Defect; Development; Electrophysiology (science); Emotional; Ethnic Origin; Etiology; Event; Financial cost; Fire - disasters; Frequencies; Gestational Age; HCN1 channel; Health; Health Care Costs; Hormonal; Hospitalization; Income; Infection; Ion Channel; Length; Life; Lung diseases; Measures; Mediating; Medical; Membrane; Membrane Potentials; Mental Retardation; Messenger RNA; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Muscle; Muscle Contraction; Myometrial; Neonatal; Neurodevelopmental Disability; Pacemakers; Patient currently pregnant; Perinatal Care; Physiological; Pilot Projects; Play; Polymerase Chain Reaction; Pregnancy; Pregnant Uterus; Premature Birth; Premature Infant; Premature Labor; Process; Property; Protein Isoforms; Recording of previous events; Regulation; Relative (related person); Resistance; Rest; Risk; Risk Factors; Role; Second Messenger Systems; Signal Transduction; Speed; Testing; Therapeutic Intervention; Time; Tissues; Transcript; Up-Regulation; Uterine Contraction; Uterus; Week; base; cost; deafness; density; infancy; mRNA Expression; mortality; myometrium; neonatal morbidity; novel; prevent; response; second messenger; social; therapeutic target; therapy design

DESCRIPTION (provided by applicant): Preterm birth (PTB), prior to the 37th week of gestation, significantly increases the risk of long-term complications such as neurodevelopmental disabilities, mental retardation, cerebral palsy, blindness, deafness and respiratory diseases, as well as communication and behavioral difficulties. Although some risk factors are known, 30-50% of spontaneous PTBs have an unknown etiology. Uterine contraction, like all smooth muscle contraction, is primarily an electromechanical event, i.e., an electrical signal initiates contraction. Although hormonal and biochemical pathways play key roles in developing parturition conditions, the speed and co-ordination of uterine excitation-contraction coupling indicates that the short-term coordinating signals for excitation in labor are carried by ion channels. The alteration of the electrical behavior of the myometrium during gestation must arise from changes in the expression level or behavior of the contributing ion channels. Spontaneous PTB therefore reflects abnormal timing in the development of the electrical activity of the uterus. Contraction during parturition results from rhythmic electrical activity (pacemaking) intrinsic to myometrium. One of the fundamental components of excitation-contraction coupling is the initiating depolarization, i.e., the "pacemaker" current. This proposal is based on my findings of a potential molecular basis for a uterine pacemaker current. My preliminary data show a unique class of ion channels, Hyperpolarization-activated Cyclic Nucleotide-sensitive (HCN) Cation Non-selective channels, in the uterus. In other tissues, these channels set the resting potential and generate rhythmic firing activity, i.e., are involved in pacemaking and automaticity. My preliminary data show that HCN1 mRNA expression is upregulated ~150 fold and HCN4 transcript is downregulated ~50 fold in late gestation relative to non-pregnant myometrium. HCN1 channels activate ~10 fold faster and are activated at a potential ~ 30 mV more depolarized than HCN4 channels, suggesting a major increase in HCN-mediated spontaneous electrical activity in late gestation. This dramatic pregnancy related upregulation of the HCN channel isoform which is most easily and rapidly activated (HCN1), is hypothesized to result in increased spontaneous myometrial excitation and consequently contraction. My hypothesis is that the upregulation of HCN1 mRNA contributes to pacemaking in the pregnant uterus. The aim of this proposal is to molecularly identify HCN channel isoforms in the myometrium and to electrophysiologically identify and characterize the corresponding cellular currents. Preterm birth results in enormous medical, social, emotional and financial costs. Currently, there are no effective ways to prevent preterm birth. Identification of an ion channel which is the uterine pacemaker offers the opportunity for designing interventions to prevent and delay preterm labor. Preterm birth results in enormous medical, social, emotional and financial costs. Currently, there are no effective ways to prevent preterm birth. Identification of an ion channel which is the uterine pacemaker offers the opportunity for designing interventions to prevent and delay preterm labor.

描述（由申请人提供）：妊娠第37周之前的早产（PTB），会显著增加长期并发症的风险，如神经发育障碍、智力迟钝、脑瘫、失明、耳聋和呼吸系统疾病，以及沟通和行为困难。虽然一些危险因素是已知的，但30-50%的自发性pbs病因不明。子宫收缩，像所有的平滑肌收缩一样，主要是一个机电事件，即电信号引发收缩。虽然激素和生化途径在分娩条件的形成中起着关键作用，但子宫兴奋-收缩耦合的速度和协调表明，分娩过程中兴奋的短期协调信号是由离子通道携带的。妊娠期子宫肌层电行为的改变一定是由离子通道表达水平或行为的改变引起的。因此，自发性PTB反映了子宫电活动发展的异常时间。分娩时的收缩是由子宫肌层固有的节律性电活动（起搏）引起的。激发-收缩耦合的一个基本组成部分是初始去极化，即“起搏器”电流。这个建议是基于我对子宫起搏器电流的潜在分子基础的发现。我的初步数据显示子宫内有一类独特的离子通道，超极化激活的环核苷酸敏感（HCN）阳离子非选择性通道。在其他组织中，这些通道设定静息电位并产生有节奏的放电活动，即参与起搏和自动性。我的初步数据显示，与未怀孕的子宫肌膜相比，妊娠后期HCN1 mRNA表达上调约150倍，HCN4转录下调约50倍。HCN1通道的激活速度比HCN4通道快10倍，激活电位比HCN4通道去极化快30 mV，表明妊娠后期HCN1介导的自发电活动显著增加。最容易和最迅速激活的HCN通道异构体（HCN1）的这种戏剧性的妊娠相关上调被认为会导致自发性肌层兴奋增加，从而导致收缩。我的假设是，HCN1 mRNA的上调有助于怀孕子宫的起搏。本提案的目的是分子鉴定肌层中的HCN通道异构体，并从电生理学上鉴定和表征相应的细胞电流。早产造成了巨大的医疗、社会、情感和经济成本。目前，还没有有效的方法来预防早产。子宫起搏器离子通道的识别为设计预防和延迟早产的干预措施提供了机会。早产造成了巨大的医疗、社会、情感和经济成本。目前，还没有有效的方法来预防早产。子宫起搏器离子通道的识别为设计预防和延迟早产的干预措施提供了机会。